Project Summary?Abstract Despite the development of novel agents for the treatment of Multiple myeloma (MM), a disseminated plasma cell malignancy, the disease remains incurable affecting ~65,000 patients in the US and causing over 10,000 deaths yearly. There is an urgent need for new, innovative therapies that can have long term impact for patients with relapsed or refractory MM. In a clinical trial at Mayo, it was recently shown that oncolytic virotherapy could induce remission in MM patients demonstrating the first successful utilization of single-shot systemic oncolytic therapy to treat disseminated cancer with minimal and short-lived clinical toxicities. We propose to build on this clinical success, utilizing a novel oncolytic agent, Vesicular stomatitis virus (VSV), an RNA virus, has several biological features making it particularly suited to treat human cancer: (i) it is a rapidly replicating, highly immunogenic virus that mediates tumor destruction by direct cytolysis and robust stimulation of antitumor immunity, (ii) Low pre-existing immunity to VSV in the general population, (iii) VSV grows to high titers allowing large-scale clinical grade virus manufacture & (iv) VSV is generally nonpathogenic in humans. Finally, myeloma cells are especially susceptible to VSV oncolysis in vitro & in myeloma mouse models. The demonstrated potent oncolytic efficacy of VSV in cancer models prompted a collaborative effort to clinically translate this promising new therapy. This has led to successful completion of preclinical toxicology studies, GMP virus manufacture, and initiation of a Phase I clinical trial evaluating intratumoral VSV-hIFN? therapy in Hepatocellular carcinoma (HCC) patients. We have developed a novel recombinant VSV expressing Interferon-? (IFN?) and the sodium iodide symporter (NIS), VSV-IFN?-NIS, for intravenous (IV) treatment of disseminated myeloma. Preclinical studies showed that a single IV dose of VSV-hIFN?-NIS is curative in an immune competent syngeneic myeloma mouse model. Murine IFN? expression enhances tumor selectivity and stimulates antitumor immunity. NIS expression allows noninvasive and serial imaging of virus replication, enabling meaningful studies of VSV pharmacodynamics in vivo and potential addition of radiation therapy when combined with the beta particle emitting isotope 131I. Additional toxicology and veterinary studies indicate a safe dose of VSV-hIFN?-NIS that can be safely administered systemically in tumor bearing mice and client- owned dogs with spontaneous hematologic malignancies respectively. The overall goal of this proposal is evaluation and optimization of systemic VSV-IFN?-NIS therapy for patients with relapsed/refractory myeloma.